Intramuscular application

The most widely-used testosterone substitution therapy is the intramuscular injection of testosterone esters. Unmodified testosterone has a half-life of only ten minutes and would have to be injected very frequently. Esterification of the testosterone molecule at position 17, e.g., with propionic or enanthic acid, prolongs the activity of testosterone in proportion to the length of the side chain when administered intramuscularly (Junkmann 1952; 1957). The deep intramuscular injection of testosterone esters in oily vehicle is generally safe and well tolerated, but can cause minor side-effects such as local pain (Mackey etal. 1995).

Studies applying gas chromatography-mass spectrometry that allow discrimination between endogenous testosterone and exogenously administered deuteriumlabelled testosterone propionate-19,19,19-d3 and its metabolite testosterone-19,19,19-d3 were able to show that after intramuscular administration, the testosterone ester is slowly absorbed into the general circulation and then rapidly converted to the active unesterified metabolite (Fujioka et al. 1986). The observation that the duration at the injection site is the major factor determining the residence time of the drug in the body agrees with pharmacokinetic studies in rats showing that the androgen ester 19-nortestosterone decanoate, when injected into the musculus gastrocnemius of the rat in vivo, is absorbed unchanged from the injection depot in the muscle into the general circulation according to firstorder kinetics with a long half-life of 130 h (van der Vies 1965). Comparisons of the absorption kinetics of different testosterone esters clearly show that the half-lives of the absorption of the esters increase when the esterified fatty acids have a longer chain (van der Vies 1985). In addition, pharmacokinetics are influenced by the oily vehicle, the injection site and the injection volume (Minto et al. 1997).

After absorption from the intramuscular depot, the testosterone ester is rapidly hydrolysed in plasma, as could be shown by in vitro rat studies (van der Vies 1970) and in vivo human studies (Fujioka etal. 1986). The rate ofhydrolysis again depends on the structure of the acid chain, but this process is much faster than release from the injection depot (van der Vies 1985). The metabolism of the testosterone ester to the unesterified testosterone occurs rapidly so that testosterone enanthate or testosterone have nearly identical intravenous pharmacokinetics (Sokol and Swerdloff 1986). Similarly, the duration of action of the orally effective ester testosterone undecanoate seems to be dependent on the duration of absorption of the uncleaved lipophilic testosterone undecanoate via the ductus thoracicus from the gut (Maisey etal. 1981; Sch├╝rmeyer etal. 1983).

In men treated with testosterone, the testosterone concentration measurable in the serum is the sum of endogenous testosterone and exogenous testosterone hydrolysed from the injected ester. Hypogonadal patients are characterized by impaired or absent endogenous testosterone secretion; exogenous testosterone administration can further suppress endogenous testosterone secretion only to a limited degree, if at all. Accordingly, in hypogonadal patients the serum concentration versus time profile is mainly a reflection of the pharmacokinetics of exogenously administered testosterone ester alone. In this chapter the evaluation of pharmacokinetic parameters for different testosterone esters is based on the increases of testosterone serum concentrations over basal levels in hypogonadal patients.

Table 14.2 Comparative pharmacokinetics of different testosterone esters after intramuscular injection to hypogonadal patients

Testosterone ester

Terminal elimination half-life (d)

Testosterone propionate

0.8

Testosterone enanthate

4.5

Testosterone buciclate

29.5

Testosterone undecanoate

33.9

Fig. 14.4 Single-dose pharmacokinetics of testosterone propionate in seven hypogonadal patients.

Closed circles, mean ┬▒ SEM of testosterone serum concentrations actually measured; curve, best-fitted pharmacokinetic profile.

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